Method and Device for Cleaning an Absorptive Polyester

ABSTRACT

In a method for cleaning an absorptive polyester, the polymer is dissolved in a first solvent ( 12 ) and subsequently the polymer solution is brought into tight contact with a second solvent ( 41 ) in a turbulent shear field under the influence of strong shear forces. Here, the second solvent ( 41 ) represents a non-solvent for the absorptive polyester and is mixable with the first solvent ( 12 ) to an unlimited extent. Subsequently, the polymer suspension resulting from the addition of the second solvent ( 41 ) is conveyed onto or into a rotating, cylindrical screen body ( 71 ) of a drum shear screen ( 70 ) and then the moist polymer mass is removed from the screen body ( 71 ) and subsequently dried. The method is suitable for the production of absorptive polyester with a high degree of quality and may be performed in a cost-effective fashion on an industrial scale as well.

The invention relates to a process for purifying a resorbable polyester,the polymer being dissolved in a first solvent and subsequently thepolymer solution being brought into intimate contact with a secondsolvent under the action of high shear forces in a turbulent shearfield, the first solvent being a “genuine” solvent and the secondsolvent being a non-solvent for the resorbable polyester and beingunlimitedly miscible with the first solvent.

Furthermore the invention also relates to a resorbable polyester whichis purified using the process and to the use thereof.

The invention further relates to a purification device for purifying aresorbable polyester that contains as its main components a dissolvingvessel in which the polymer is dissolved in a first solvent, aseparation device for separating a moist polymer mass from a polymersuspension and a dryer for drying the polymer mass.

Resorbable polyesters in the sense of the invention are homopolymers orcopolymers based on lactide (L-lactide, D-lactide, DL-lactide,meso-lactide), glycolide, epsilon-caprolactone, dioxanone, trimethylenecarbonate, delta-valerolactone, gamma-butyrolactone, and similarpolymerisable heterocycles. The polymers can either be composed of oneor else of a plurality of different monomer modules or optionallycontain further modules in the polymer chain, such as for example unitsof ethylene glycol.

Preferred according to the invention are homopolymers of D,L-lactide,copolymers of D,L-lactide and glycolide of differing composition andblock copolymers of the aforementioned polyester units and polyethyleneglycol.

Resorbable polyesters are raw materials which are widely used for theproduction of resorbable, surgical implants and also as a pharmaceuticalauxiliary for the formulation of parenteral release systems. Forexample, poly(lactides) and other resorbable polyesters are used insurgical implants for the fixing of bone fractures, in reticula andmembranes for controlled tissue regeneration and in microcapsules andimplants for subcutaneous or intramuscular injection, in particular forthe controlled release of active ingredients. After implantation orinjection into the body, resorbable polymers are broken down intooligomers in a slow hydrolytic reaction. Hydrolysis end products such aslactic acid or glycolic acid are metabolised into carbon dioxide andwater.

The synthesis of resorbable polyesters is known in the art. They can beprepared by polycondensation from hydroxycarboxylic acids such as lacticacid and/or glycolic acid. Another frequently taken synthesis pathway isthe ring-opening polymerisation of the corresponding heterocycles.

Irrespective of the synthesis pathway, the crude polymers always containa specific content of non-converted monomers that frequently cannot bereduced below a value of from 1 to 3% even if the correspondingsynthesis processes are optimised. The reason for this is thatring-opening polymerisation is an equilibrium reaction and even duringpolycondensation the linear polyester is present in equilibrium with thecorresponding hydroxycarboxylic acids.

The presence of monomers in the polymers is extremely problematic forthe following reasons:

-   -   a) Because cyclic monomers are much more unstable in relation to        hydrolytic decomposition than linear polyesters, they decompose        more rapidly than polyesters on ingress of moisture. The        hydrolytic decomposition generates acid equivalents which,        again, the hydrolytic decomposition of the polyesters also        catalyses. The implantation of monomer-containing polyesters        would therefore lead to a greatly accelerated breakdown of the        material in the body.    -   b) For the same reason, the stability in storage of        monomer-containing polyesters and implants or pharmaceutical        formulations produced therefrom is markedly impaired.    -   c) The stability of resorbable polyesters is also impaired        during thermoplastic processing if residual contents of monomers        are present.    -   d) The encapsulation behaviour of non-purified polyesters is        different from that of purified polyesters, as are the release        behaviour and the breakdown behaviour. Encapsulated active        ingredients, such as peptides, can become damaged or destroyed        as a result of the greater amount of free acid compared to        purified polymers.    -   e) During the synthesis reactions, the residual monomer content        of the crude polymer is often difficult to control. Variability        in the residual monomer content then automatically also leads to        intolerable batch-to-batch variations in the breakdown rate, the        stability in storage and the processing stability, so materials        of reproducible quality cannot be obtained without a subsequent        purification step to reduce the amount of residual monomers.

Purification processes for separating residual monomers from resorbablepolyesters are also known in the art.

Monomers can be removed from partially crystalline polyesters usingextraction processes. Suitable for this purpose are solvents whichdissolve the monomer but do not dissolve the polymer. Suitable examplesinclude organic solvents such as n-hexane, cyclohexane, methanol,ethanol, acetone or ethyl acetate. EP 0456246 discloses for example anextraction process for resorbable polyesters that uses carbon dioxide asthe solvent.

Amorphous polyester can generally not be purified by extractionprocesses, as the relevant solvents either also dissolve the polymer orat least cause it to swell. If supercritical or pressure-liquefiedcarbon dioxide is used, the polymer mass expands greatly when thepressure is relieved, and this also prevents a process of this type frombeing carried out. The prior art discloses a number of reprecipitationprocesses for the purification of amorphous polyesters. These involvedissolution of the crude polymer in a suitable solvent. The addition ofa large excess of a non-solvent, which is however miscible with thesolvent, causes precipitation of the polymer. For example, thereprecipitation of a poly(L-lactide)poly(ethyleneglycol)-poly(L-lactide) by dissolution in chloroform and precipitationin methanol or methanol/chloroform mixtures is disclosed (J. Matsumototet al.; Int. J. of Pharm.; 185; 1999; 93-101). The disclosedreprecipitation processes have the drawback of using a huge amount oforganic solvents and, in addition, the solid/liquid phase separation,and thus the product isolation, is extremely difficult. This is inparticular due to the fact the polyesters tend to agglomerate at thecontact point at which the polymer solution enters into contact with thenon-solvent. Application on an industrial scale is therefore difficult.

U.S. Pat. No. 4,810,775 discloses a purification process for resorbablepolyesters having crystallinity of up to 20%, the polymer beingdissolved in a solvent, the polymer solution subsequently being broughtinto intimate contact with a precipitant under the action of high shearforces in a turbulent shear field. The turbulent shear field isgenerated by a device consisting of a two-fluid nozzle and of acontainer which is filled with precipitant and into which the two-fluidnozzle protrudes, so the precipitating polymer is broken down into verysmall particles. However, it is not disclosed how a process of this typecan be carried out economically on a large scale. The phase separationof the polymer suspension formed during the reprecipitation is carriedout either in a centrifuge or by collection in receptacles which, owingto the large amount of solvent required, must be large even inrelatively small batch sizes.

The object of the invention is therefore to provide an improvedpurification process for purifying a resorbable polyester, in particularan amorphous polyester, of the type mentioned at the outset that allowsa resorbable polyester of high and reproducible quality to be obtainedeven on an industrial scale. It is furthermore the object of theinvention to provide a corresponding device for the process according tothe invention.

The object concerning the process is achieved according to the inventionin that subsequently the polymer suspension, which is formed by theaddition of the second solvent, is conveyed onto or into a rotating,cylindrical screen body of a drum shear screen and subsequently themoist polymer mass is separated from the screen body and subsequentlydried thereon.

This provides a continuously operating separation process which allowsthe polymer suspension to be separated with high reproducibility intothe solid and liquid phase. The continuous mode of operation allowsbatches of constant quality to be provided irrespective of the amount.

In terms of the process, provision is made for the first solvent used tobe acetone, ethyl acetate, 1,4-dioxane, dimethylacetamide,tetrahydrofuran, toluene, dimethylformamide, dimethylsulphoxide,hexafluoroisopropanol or another halogenated hydrocarbon or a mixture ofthe aforementioned solvents. A suitable solvent is thus provideddepending on the type of polyester and the inherent viscosity of thepolyester in solution. Acetone, chloroform or dichloromethane have beenfound to be particularly suitable as the first solvent.

Preferably, the second solvent used is ethanol, methanol or water or amixture of the aforementioned solvents. Particularly effectiveprecipitation reactions can thus be achieved, depending on the firstsolvent used, water in particular being used as the second solvent.Water is non-toxic and non-explosive but cost-effective and particularlyenvironmentally acceptable.

According to a development, the resorbable polyester which is dissolvedin the first solvent is filtered and subsequently mixed with the secondsolvent via a two-fluid nozzle. This produces an intimate contact underthe action of high shear forces in the turbulent shear field, as aresult of which optimum thorough mixing is achieved. Alternativeintensive thorough mixing can also be achieved if both media areinjected from two separate nozzles into a flow tube and a fluidised bedis generated at the contact point by means of a rapidly rotatingstirrer.

Advantageously, the moist polymer mass is separated effectively by meansof gravity and by means of one or more helically attached conveyor railsand/or guide blades inside the rotating, cylindrical screen body. Thisprovides restricted conveyance which allows the polymer mass to beconveyed continuously, for example into a receptacle.

In order to obtain a low residual moisture or residual solvent content,for drying the moist polymer mass, nitrogen or air is expediently passedtherethrough in a dryer.

The process according to the invention can be used to purifycost-effectively and with constant quality, in particular, resorbablepolyesters having an amorphous or partially crystalline structure.

Resorbable polyesters purified in this way preferably contain one ormore units derived from lactide (L-lactide, D-lactide, DL-lactide,meso-lactide), glycolide, trimethylene carbonate, epsilon-caprolactone,gamma-butyrolactone, dioxanone, delta-valerolactone and/or similarpolymerisable heterocycles and/or polyethylene glycols. Particularlypreferred is a resorbable polyester which is composed of D,L-lactide orcopolymers of D,L-lactide and glycolide having any desired compositionor a block copolymer of D,L-lactide, or D,L-lactideco-glycolide havingany desired composition and polyethylene glycol.

The residual monomer content, after the purification has been carriedout using the process according to the invention, is less than 1%, inparticular less than 0.5%, a residual monomer content of below 0.1%being achievable.

After the drying, the solvent and/or moisture content of the resorbablepolyester is less than 2%, values of below 1%, in particular values ofbelow 0.5% being achieved under beneficial settings. If driedparticularly intensively, the solvent and/or moisture content of theresorbable polyester is <0.1%.

A particularly preferred use of the resorbable polyester provides forthe production of pharmaceutical formulations or resorbable implants.

The object concerning the purification device is achieved according tothe invention in that the separation device is constructed as a drumshear screen comprising a rotating, cylindrical screen body.

With this type of separation device, such as has previously been usedfor example in other fields for the continuous dehydration of high solidloads, it has surprisingly been found that the device allows polymersuspensions formed from a precipitation reaction to be separatedcost-effectively and at constant quality into a polymer mass and intosolvent residues even if the throughput fluctuates.

Conveyor rails and/or guide blades inside the cylindrical screen bodyallow, in conjunction with the rotational movement of the screen body,the polymer mass to be conveyed continuously into, for example, areceptacle.

In an advantageous embodiment the drum shear screen has a suctiondevice, in particular comprising a suction nozzle, above the rotating,cylindrical screen body in an upper housing cover. This provides removalof solvent vapours by suction, and this is particularly advantageous if,for example, acetone, ethanol or methanol is used, as the suction deviceallows the explosion protection class of the surrounding building to bereduced.

A dryer which is configured as a fluidised bed dryer, circulating airdryer or tubular-flow dryer is particularly suitable for effectivedrying of the moist polymer mass. The dryer has in a preferredembodiment a conical portion and a cylindrical portion, intensiveswirling of the polymer mass to be dried being achieved in the conicalportion of the dryer owing to the drying agent, for example nitrogen orair, which flows in from below. In order to reduce agglomeration, agrater is provided for the polymer. During drying, the polymer mass tobe dried can be removed from the dryer and grated via the grater, afterwhich the drying is continued.

In order to prevent the polymer from passing out of the dryer into asupply system, the dryer has inside the cylindrical portion at least onescreen insert. For collecting the purified resorbable polyester, thedryer expediently comprises a filter bag. A swivel bearing of the dryerin a frame allows the dryer to be tilted, thus allowing the filter bagwhich is fastened to the dryer on the end side and comprises the driedpolymer powder easily to be removed. Moreover the polymer mass to bedried can be mixed thoroughly more easily during the drying process.

According to a further configuration at least the product-guiding partsof the drum shear screen and of the dryer are made of stainless steel,thus ensuring high product quality with regard to pharmacologicalrequirements.

It will be understood that the above-mentioned features and those whichwill be described hereinafter can be used not only in the respectivelyspecified combination but rather also in other combinations. The scopeof the invention is defined merely by the claims.

The invention will be described hereinafter in greater detail using anexemplary embodiment and with reference to the associated drawings, inwhich:

FIG. 1 Is a schematic view of a purification device for resorbablepolyesters for carrying out the process according to the invention,

FIG. 2 is a perspective exploded view of the drum shear screen accordingto FIG. 1, and

FIG. 3 is a perspective view of the dryer according to FIG. 1.

A purification device 1 comprises as its main component for a firstprocess step a dissolving vessel 10 in which a polyester crude product11 to be purified is placed. A typical size of the dissolving vessel 10is in the range of from 50 to 1,000 l and can, in the case of largersystems, be as much as 2,000 l or more. The addition of a first solvent12 causes dissolution in the dissolving vessel 10 of the polyester crudeproduct 11 with the aid of a stirrer 13 and/or by constant recirculationof the solution. Impurities in the polyester crude product 11, forexample in the form of lint, are separated, for example by filtration.The following solvents have, for example, been found to be preferredfirst solvents 12: acetone, ethyl acetate, 1,4-dioxane,dimethylacetamide, tetrahydrofuran, toluene, dimethylformamide,dimethylsulphoxide, hexafluoroisopropanol or another halogenatedhydrocarbon or a mixture of the aforementioned solvents. In theresorbable polyesters, acetone, chloroform or dichloromethane haveproven particularly suitable as first solvents 12.

A pump, for example a diaphragm pump, is used to pump the polymersolution via a filter 30 containing a fine-meshed screen, preferablymade of stainless steel. In this step insoluble impurities are separatedoff. Typical mesh sizes are in this case a few μm, typically in therange of from 1 to 10 μm.

Subsequently, the polymer solution is intensively mixed via a two-fluidnozzle 40 by means of a second solvent 41, which is a non-solvent forthe polymer, and the polymer suspension resulting therefrom is guidedinto the interior of a rotating screen body 71 of a drum shear screen 70via a conveyor 60, in the simplest case directly or via a flow tube or apipe, wherein the conveyance can be carried out by means of gravity,conventional pumps or by pressurisation by means of a gas. The secondsolvent 41 used is ethanol, methanol or water or a mixture of theaforementioned solvents for precipitation. Water is a particularlypreferred second solvent 41 owing to its toxicological safeness andenvironmental acceptability.

Inside the rotating screen body 71 of the drum shear screen 70, thepolymer suspension can be separated into the solvent mixture and intothe precipitated polymer mass. One or more helically attached guiderails and/or guide blades 72 inside the screen body 71 subject thepolymer mass to restricted conveyance, so the polymer mass istransported to a solid outlet 75. The solvent mixture can in this caseflow away downward through a liquid outlet 73. Solvent vapours can beremoved by suction via a suction device 74, for example a suctionnozzle, in a housing cover 76 of the drum shear screen 70 above thescreen body 71, and this is advantageous with regard to the explosionprotection class of the surrounding building.

The still-moist polymer mass which collects at the solid outlet 75 istransported using a solid conveyor 80 either directly into a dryer 90 orinto a collection vessel. Batchwise filling of the dryer 90 from thecollection vessel is possible in addition to continuous feeding. Thedryer 90 has a conical portion 95 and a cylindrical portion 96. At leastone screen insert 94 is provided inside the cylindrical portion 96. Thedrying agent 91, for example nitrogen or air, is introduced laterallyfrom below into the conical portion 95 of the dryer 90, so intensiveswirling is achieved inside the dryer 90. The dryer 90 has a filter bag92 for collecting the purified and dried resorbable polyester.

In the configuration of the drum shear screen 70 according to FIG. 2,there may be seen on the inside the rotating screen body 71 into whichthe polymer suspension can be introduced via a U-shaped channel. Thescreen body 71 is positioned slightly obliquely. One or more helicallyattached guide rails and/or guide blades 72 inside the screen body 71cause the restricted conveyance of the polymer mass to the solid outlet75. Solvent vapours are removed by suction via the suction device 74 inthe housing cover 76 of the drum shear screen 70 above the screen body71. The screen body 71 is closed on its back to prevent the inside ofthe screen from becoming contaminated with abraded material from thedrive unit. The back can be opened for purification purposes.

The dryer 90 according to FIG. 3, which is arranged in a movable frame97, can be tilted by means of a swivel bearing 93. The filter bag 92 isnot shown. Moreover at least the product-guiding parts of the drum shearscreen 70 and of the dryer 90 are made of stainless steel.

The process according to the invention will be described hereinafter:

The polyester crude product 11 is dissolved with the previouslycalculated amount of acetone as the first solvent 12. The polyestercrude product 11 is weighed out and placed in the dissolving vessel 10.The calculated amount of acetone is added and the crude productdissolved by recirculation within approx. 24-72 hours. The mixing ratiois dependent on the starting substances used (monomers or heterocycles)and the inherent viscosity of the crude product and is, for example in acopolymer of D,L-lactide and glycolide; 50:50 mol %; inherent viscosityof 0.5 dl/g measured as a 0.1% solution in chloroform; solution forprecipitation is dispensed with, 8% by weight of polymer in acetone.

The polymer solution is conveyed into the two-fluid nozzle 40 by meansof the pump 20 via a filter 30 made of stainless steel having a meshsize of 5 μm and a flowmeter. The flow is dependent on the nature of thecrude product used and is generally up to 20 l/h. This figure relates toa flowmeter which is adjusted to the density of acetone. The differingdensities of the polymer solutions to be precipitated prevent preciseflow measurement (except for mass flowmeters). In the two-fluid nozzle40 the polymer solution is injected into a water jet at a flow rate ofapprox. 700-1000 l/h, the dissolved crude product precipitatingimmediately in the form of flakes or fibres.

The suspension, consisting of water, product flakes, monomer andacetone, is guided into the drum shear screen 70 via a pipe. In thiscase the suspension is guided into the rear region of the drum shearscreen 70. As a result of the rotational movement, the dischargingwater/acetone mixture, which contains the monomers to be separated off,initially forms a product layer at this location. If the product layeris sufficiently heavy, it becomes detached from the wall and forms aproduct cluster (snowball system). As a result of the guide blades 72,which run obliquely forward, and the rotational movement, these productclusters are slowly conveyed toward the solid outlet 75 in the screenbody 71. The water/acetone mixture is separated off, on the one hand, bymeans of gravity and, on the other hand, by wedge-shaped screen profilebars and the Coand{hacek over (a)} effect resulting therefrom.

The solid is guided into the dryer 90 or the collection vessel by meansof the solid conveyor 80. In the dryer 90, which is configured as atubular-flow dryer, the moist polymer mass is dried by means of athroughflow of air or nitrogen.

1. A process for purifying a resorbable polyester comprising the stepsof: (a) dissolving the resorbable polyester in a first solvent (12) toform a polymer solution, wherein the first solvent (12) is a genuinesolvent; (b) intimately contacting the polymer solution with a secondsolvent (41) under action of high shear forces in a turbulent shearfield to form a polymer suspension, wherein the second solvent (41) is anon-solvent for the resorbable polyester and is unlimitedly misciblewith the first solvent (12); (c) conveying the polymer suspension ontoor into a rotating, cylindrical screen body (71) of a drum shear screen(70) to form a moist polymer mass; (d) separating the moist polymer massfrom the screen body (71); and (e) drying the polymer mass.
 2. Theprocess according to claim 1, wherein the first solvent (12) is acetone,ethyl acetate, 1,4-dioxane, dimethylacetamide, tetrahydrofuran, toluene,dimethylformamide, dimethylsulphoxide, hexafluoroisopropanol or anotherhalogenated hydrocarbon or a mixture of the aforementioned solvents. 3.The process according to claim 2, wherein the first solvent (12) isacetone, chloroform or dichloromethane.
 4. The process according to anyone of claims 1 to 3, wherein the second solvent (41) is ethanol,methanol or water or a mixture of the aforementioned solvents.
 5. Theprocess according to claim 1, wherein the resorbable polyester dissolvedin the first solvent (12) is further filtered and subsequently mixedwith the second solvent (41) via a two-fluid nozzle (40).
 6. The processaccording to claim 1, wherein the moist polymer mass is separated bymeans of gravity and by means of one or more helically attached conveyorrails and/or guide blades (72) inside the rotating, cylindrical screenbody (71).
 7. The process according to claim 1, wherein the drying stepinvolves passing nitrogen or air through the polymer mass in a dryer(90).
 8. The process according to claim 1, wherein the resorbablepolyester is an amorphous or partially crystalline polyester.
 9. Theprocess according to claim 1, wherein the resorbable polyester containsone or more units derived from lactide (L-lactide, D-lactide,DL-lactide, meso-lactide), glycolide, trimethylene carbonate,epsilon-caprolactone, gamma-butyrolactone, dioxanone,delta-valerolactone and/or similar polymerisable heterocycles and/orpolyethylene glycols.
 10. The process according to claim 1, wherein theresorbable polyester is composed of copolymers of lactide and glycolideand/or polyethylene glycols having any desired composition.
 11. Theprocess according to claim 1, wherein resorbable polyester has aresidual monomer content of less than 1%.
 12. The process according toclaim 1, wherein the resorbable polyester has a solvent and/or moisturecontent of less than 2%.
 13. A pharmaceutical formulation or aresorbable implant containing a resorbable polyester made by the processaccording to claim
 1. 14. A purification device for purifying aresorbable polyester that contains as its main components a dissolvingvessel (10) in which the polymer is dissolved in a first solvent (12), aseparation device for separating a moist polymer mass from a polymersuspension and a dryer (90) for drying the polymer mass, characterisedin that the separation device is constructed as a drum shear screen (70)comprising a rotating, cylindrical screen body (71).
 15. Thepurification device according to claim 14, characterised in that thecylindrical screen body (71) has in its interior conveyor rails and/orguide blades (72).
 16. The purification device according to claim 14,characterised in that the drum shear screen (70) has a suction device(74), in particular comprising a suction nozzle, above the rotating,cylindrical screen body (71) in an upper housing cover (76).
 17. Thepurification device according to claim 14, characterised in that thedryer (90) is a fluidised bed dryer, a circulating air dryer or atubular-flow dryer.
 18. The purification device according to claim 14,characterised in that the dryer (90) has a conical portion (95) and acylindrical portion (96).
 19. The purification device according to claim14, characterised in that the dryer (90) comprises inside thecylindrical portion (96) at least one screen insert (94).
 20. Thepurification device according to claim 14, characterised in that thedryer (90) has a filter bag (92) for collecting the purified resorbablepolyester.
 21. The purification device according to claim 14,characterised in that the dryer (90) is provided with a swivel bearing(93).
 22. The purification device according to claim 14, characterisedin that at least the product-guiding parts of the drum shear screen (70)and of the dryer (90) are made of stainless steel.